Tag: creatine

Cerebrospinal fluid metabolomics, lipidomics and serine pathway dysfunction in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS)

Abstract:

We proposed that cerebrospinal fluid would provide objective evidence for disrupted brain metabolism in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS). The concept of postexertional malaise (PEM) with disabling symptom exacerbation after limited exertion that does not respond to rest is a diagnostic criterion for ME/CFS. We proposed that submaximal exercise provocation would cause additional metabolic perturbations.

The metabolomic and lipidomic constituents of cerebrospinal fluid from separate nonexercise and postexercise cohorts of ME/CFS and sedentary control subjects were contrasted using targeted mass spectrometry (Biocrates) and frequentist multivariate general linear regression analysis with diagnosis, exercise, gender, age and body mass index as independent variables. ME/CFS diagnosis was associated with elevated serine but reduced 5-methyltetrahydrofolate (5MTHF).

One carbon pathways were disrupted. Methylation of glycine led to elevated sarcosine but further methylation to dimethylglycine and choline was decreased. Creatine and purine intermediates were elevated. Transaconitate from the tricarboxylic acid cycle was elevated in ME/CFS along with essential aromatic amino acids, lysine, purine, pyrimidine and microbiome metabolites. Serine is a precursor of phospholipids and sphingomyelins that were also elevated in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls.

The findings differ from prior hypometabolic findings in ME/CFS plasma. The novel findings generate new hypotheses regarding serine-folate-glycine one carbon and serine-phospholipid metabolism, elevation of end products of catabolic pathways, shifts in folate, thiamine and other vitamins with exercise, and changes in sphingomyelins that may indicate myelin and white matter dysfunction in ME/CFS.

Source: Baraniuk JN. Cerebrospinal fluid metabolomics, lipidomics and serine pathway dysfunction in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS). Sci Rep. 2025 Mar 3;15(1):7381. doi: 10.1038/s41598-025-91324-1. PMID: 40025157. https://www.nature.com/articles/s41598-025-91324-1 (Full text)

Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics–Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort (“fatigue”) that does not respond to rest. Cerebrospinal fluid was examined as a proxy for brain metabolite and lipid flux and to provide objective evidence of pathophysiological dysfunction. Two cohorts of ME/CFS and sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). Cerebrospinal fluid metabolites and lipids were quantified by targeted Biocrates mass spectrometry methods.
Significant differences between ME/CFS and control, non-exercise vs. post-exercise, and by gender were examined by multivariate general linear regression and Bayesian regression methods. Differences were found at baseline between ME/CFS and control groups indicating disease-related pathologies, and between non-exercise and post-exercise groups implicating PEM-related pathologies.
A new, novel finding was elevated serine and its derivatives sarcosine and phospholipids with a decrease in 5-methyltetrahydrofolate (5MTHF), which suggests general dysfunction of folate and one-carbon metabolism in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. In general, the frequentist and Bayesian analyses generated complementary but not identical sets of analytes that matched the metabolic modules and pathway analysis. Cerebrospinal fluid is unique because it samples the choroid plexus, brain interstitial fluid, and cells of the brain parenchyma.
The quantitative outcomes were placed into the context of the cell danger response hypothesis to explain shifts in serine and phospholipid synthesis; folate and one-carbon metabolism that affect sarcosine, creatine, purines, and thymidylate; aromatic and anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, and coenzyme A in energy metabolism; and vitamin activities that may be altered by exertion. The metabolic and phospholipid profiles suggest the additional hypothesis that white matter dysfunction may contribute to the cognitive dysfunction in ME/CFS.
Source: Baraniuk JN. Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics–Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International Journal of Molecular Sciences. 2025; 26(3):1282. https://doi.org/10.3390/ijms26031282 https://www.mdpi.com/1422-0067/26/3/1282 (Full text)

The effects of 3-month supplementation with synbiotic on patient-reported outcomes, exercise tolerance, and brain and muscle metabolism in adult patients with post-COVID-19 chronic fatigue syndrome (STOP-FATIGUE): a randomized Placebo-controlled clinical trial

Abstract:

Purpose: Considering the observed gastrointestinal issues linked to post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), beneficially modulating the gut microbiota could offer a safe, cost-effective nutritional strategy. This trial aimed to evaluate the effects of medium-term synbiotic supplementation on patient-reported outcomes, exercise tolerance, and tissue metabolism in patients with post-COVID-19 ME/CFS.

Methods: Between September 2022 and December 2023, we investigated the impact of 3-month supplementation with a synbiotic mixture including L. rhamnosus DSM 32550, Humiome® L. plantarum DSM 34532, B. lactis DSM 32269, B. longum DSM 32946, fructooligosaccharides and zinc, on predetermined primary and secondary outcome measures in twenty six post-COVID-19 ME/CFS patients utilizing a parallel-group, randomized, placebo-controlled, double-blind design.

Results: Both the synbiotic and placebo intake resulted in a significant reduction in general fatigue after 3 months compared to the baseline values (P ≤ 0.05). This was accompanied by a significant interaction effect (time vs. treatment) for post-exercise malaise (P = 0.02), with synbiotic superior to placebo to attenuate post-exercise malaise. The synbiotic also demonstrated a significant advantage over placebo in increasing choline levels at the thalamus (P = 0.02), and creatine levels at left frontal white matter (P = 0.05) and left frontal grey matter (P = 0.04).

Conclusion: Taking the synbiotic mixture for three months improves tissue metabolism and mitigates clinical features of post-COVID-19 fatigue syndrome. The presented data show promise in addressing the widespread issue of ME/CFS following the COVID-19 pandemic; however, further validation is needed before endorsing the synbiotics within this clinical context. The study is registered at ClinicalTrials.gov (NCT06013072).

Source: Ranisavljev M, Stajer V, Todorovic N, Ostojic J, Cvejic JH, Steinert RE, Ostojic SM. The effects of 3-month supplementation with synbiotic on patient-reported outcomes, exercise tolerance, and brain and muscle metabolism in adult patients with post-COVID-19 chronic fatigue syndrome (STOP-FATIGUE): a randomized Placebo-controlled clinical trial. Eur J Nutr. 2024 Nov 26;64(1):28. doi: 10.1007/s00394-024-03546-0. PMID: 39592468. https://pubmed.ncbi.nlm.nih.gov/39592468/

Six-Week Supplementation with Creatine in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Magnetic Resonance Spectroscopy Feasibility Study at 3 Tesla

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic medical condition with no specific pharmacological treatment. Creatine, a nutrient essential for maintaining energy homeostasis in the cells, is a candidate for interventions in ME/CFS.

Methods: Fourteen participants with ME/CFS received supplementation with 16 g creatine monohydrate for 6 weeks. Before starting creatine and on the last day of treatment, participants underwent brain magnetic resonance spectroscopy (MRS) scanning of the pregenual anterior cingulate cortex (pgACC) and dorsolateral prefrontal cortex (DLPFC), followed by symptom, cognition, and hand-grip strength assessments.

Results: Eleven participants completed the study. Creatine treatment increased creatine concentration in both the pgACC and DLPFC (p = 0.004 and 0.012, respectively), decreased fatigue and reaction time (RT) on congruent and incongruent trials of the Stroop test (p = 0.036 and 0.014, respectively), and increased hand-grip strength (p = 0.0004). There was a positive correlation between increases in pgACC creatine and changes in RT on Stroop congruent and incongruent trials (p = 0.048 and p = 0.022, respectively). Creatine was well tolerated, and none of the participants stopped treatment.

Conclusion: Creatine supplementation over six weeks in ME/CFS patients increased brain creatine and improved fatigue and some aspects of cognition. Despite its methodological limitations, this study encourages placebo-controlled investigations of creatine treatment in ME/CFS.

Source: Godlewska BR, Sylvester AL, Emir UE, Sharpley AL, Clarke WT, Martens MAG, Cowen PJ. Six-Week Supplementation with Creatine in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Magnetic Resonance Spectroscopy Feasibility Study at 3 Tesla. Nutrients. 2024 Sep 30;16(19):3308. doi: 10.3390/nu16193308. PMID: 39408275. https://www.mdpi.com/2072-6643/16/19/3308 (Full text)

Creatine supplementation combined with breathing exercises reduces respiratory discomfort and improves creatine status in patients with long-COVID

Abstract:

Eight long-COVID patients with moderate fatigue that had lasted for ≥3 months were recruited. All patients were allocated in a double-blind parallel-group design to receive either 4 g of creatine per day plus breathing exercises (study group) or breathing exercises only (control group) for 3 months.

Creatine induced a significant increase in tissue total creatine levels for all 14 locations evaluated in the present study (P < 0.05), while its levels significantly dropped in the right frontal gray matter and left parietal mesial gray matter at follow-up in the control group (P < 0.05).

No change in time to exhaustion was demonstrated in the control group (P > 0.05), while the mean time to exhaustion was significantly improved for 54 s in the study group post-administration (P = 0.05).

These preliminary findings suggest that creatine is as an effective adjuvant therapeutic to breathing exercises for tackling the clinical features in long-COVID.

Source: Slankamenac, J; Ranisavljev, M; Todorovic, N; Ostojic, J; Stajer, V; Ostojic, SM. Creatine supplementation combined with breathing exercises reduces respiratory discomfort and improves creatine status in patients with long-COVID. Journal of Postgraduate Medicine ():, December 07, 2023. | DOI: 10.4103/jpgm.jpgm_650_23  https://journals.lww.com/jopm/abstract/9000/creatine_supplementation_combined_with_breathing.99983.aspx (Full text available as PDF file)

Effects of six-month creatine supplementation on patient- and clinician-reported outcomes, and tissue creatine levels in patients with post-COVID-19 fatigue syndrome

Abstract:

Dietary creatine has been recently put forward as a possible intervention strategy to reduce post-COVID-19 fatigue syndrome yet no clinical study so far evaluated its efficacy and safety for this perplexing condition. In this parallel-group, randomized placebo-controlled double-blind trial, we analyzed the effects of 6-month creatine supplementation (4 g of creatine monohydrate per day) on various patient- and clinician-reported outcomes, and tissue creatine levels in 12 patients with post-COVID-19 fatigue syndrome.

Creatine intake induced a significant increase in tissue creatine levels in vastus medialis muscle and right parietal white matter compared to the baseline values at both 3-month and 6-month follow-ups (p < .05). Two-way analysis of variance with repeated measures revealed a significant difference (treatment vs. time interaction) between interventions in tissue creatine levels (p < .05), with the creatine group was superior to placebo to augment creatine levels at vastus medialis muscle, left frontal white matter, and right parietal white matter.

Creatine supplementation induced a significant reduction in general fatigue after 3 months of intake compared to baseline values (p = .04), and significantly improved scores for several post-COVID-19 fatigue syndrome-related symptoms (e.g., ageusia, breathing difficulties, body aches, headache, and difficulties concentrating) at 6-month follow-up (p < .05). Taking creatine for 6 months appears to improve tissue bioenergetics and attenuate clinical features of post-COVID-19 fatigue syndrome; additional studies are warranted to confirm our findings in various post-COVID-19 cohorts.

Source: Slankamenac, J., Ranisavljev, M., Todorovic, N., Ostojic, J., Stajer, V., & Ostojic, S. M. (2023). Effects of six-month creatine supplementation on patient- and clinician-reported outcomes, and tissue creatine levels in patients with post-COVID-19 fatigue syndrome. Food Science & Nutrition, 00, 1–7. https://doi.org/10.1002/fsn3.3597 (Full text)

Sonographic Diaphragm Abnormalities are an Unexpectedly Frequent Feature of Long COVID Outpatients with Unexplained Dyspnea and Fatigue

Abstract:

Purpose: The primary aim of this study is to define the sonographic diaphragm phenotype of Long COVID rehabilitation outpatients with non-specific dyspnea and fatigue. We analyzed patients referred from a pulmonary post-COVID clinic that were lacking a specific cardiopulmonary diagnosis for their symptoms. Additionally, we report the functional outcomes of subset of patients who completed an outpatient cardiopulmonary physical therapy program.

Methods: This was a retrospective cohort study (n = 58) of consecutive patients referred for neuromuscular ultrasound assessment of diaphragm muscle using B-mode technique. Patients were recruited from a single academic hospital between February 25, 2021 and November 22, 2022.

Results: Sonographic abnormalities were identified in 57% (33/58) of patients, and in the vast majority of cases (33/33) was defined by a low diaphragm muscle thickness. Thinner diaphragm muscles are correlated with lower serum creatinine and creatine kinase values, but there was no association with markers of systemic inflammation. Thirty three patients participated in outpatient cardiopulmonary physical therapy that included respiratory muscle training, and 75.8% (25/33) had documented improvement.

Conclusion: In the outpatient rehabilitation setting, patients with Long COVID display low diaphragm muscle thickness, but intact muscle contractility, with surprising frequency on neuromuscular ultrasound. We speculate this represents a form of disuse atrophy. Also, these patients appear to have a favorable response to cardiopulmonary physical therapy that includes respiratory muscle training.

Source: Prabhav P. Deo, Joseph I. Bailey, Alexandra S. Jensen, Ellen Farr, Meghan Fahey, Matthew Isherwood, Keerthana Chakka, Lisa F. Wolfe, Ishan Roy, Marc A. Sala, Colin K. Franz. Sonographic Diaphragm Abnormalities are an Unexpectedly Frequent Feature of Long COVID Outpatients with Unexplained Dyspnea and Fatigue. medRxiv 2022.06.29.22277054; doi: https://doi.org/10.1101/2022.06.29.22277054 (Full text)

Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review

Abstract:

Creatine monohydrate (CrM) is one of the most widely used nutritional supplements among active individuals and athletes to improve high-intensity exercise performance and training adaptations. However, research suggests that CrM supplementation may also serve as a therapeutic tool in the management of some chronic and traumatic diseases. Creatine supplementation has been reported to improve high-energy phosphate availability as well as have antioxidative, neuroprotective, anti-lactatic, and calcium-homoeostatic effects. These characteristics may have a direct impact on mitochondrion’s survival and health particularly during stressful conditions such as ischemia and injury.

This narrative review discusses current scientific evidence for use or supplemental CrM as a therapeutic agent during conditions associated with mitochondrial dysfunction. Based on this analysis, it appears that CrM supplementation may have a role in improving cellular bioenergetics in several mitochondrial dysfunction-related diseases, ischemic conditions, and injury pathology and thereby could provide therapeutic benefit in the management of these conditions. However, larger clinical trials are needed to explore these potential therapeutic applications before definitive conclusions can be drawn.

Source: Marshall RP, Droste JN, Giessing J, Kreider RB. Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review. Nutrients. 2022 Jan 26;14(3):529. doi: 10.3390/nu14030529. PMID: 35276888. https://www.mdpi.com/2072-6643/14/3/529/htm (Full text)

Evidence of Clinical Pathology Abnormalities in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) from an Analytic Cross-Sectional Study

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease presenting with extreme fatigue, post-exertional malaise, and other symptoms. In the absence of a diagnostic biomarker, ME/CFS is diagnosed clinically, although laboratory tests are routinely used to exclude alternative diagnoses. In this analytical cross-sectional study, we aimed to explore potential haematological and biochemical markers for ME/CFS, and disease severity.

We reviewed laboratory test results from 272 people with ME/CFS and 136 healthy controls participating in the UK ME/CFS Biobank (UKMEB). After corrections for multiple comparisons, most results were within the normal range, but people with severe ME/CFS presented with lower median values (p < 0.001) of serum creatine kinase (CK; median = 54 U/L), compared to healthy controls (HCs; median = 101.5 U/L) and non-severe ME/CFS (median = 84 U/L).

The differences in CK concentrations persisted after adjusting for sex, age, body mass index, muscle mass, disease duration, and activity levels (odds ratio (OR) for being a severe case = 0.05 (95% confidence interval (CI) = 0.02–0.15) compared to controls, and OR = 0.16 (95% CI = 0.07–0.40), compared to mild cases). This is the first report that serum CK concentrations are markedly reduced in severe ME/CFS, and these results suggest that serum CK merits further investigation as a biomarker for severe ME/CFS.

Source: Nacul, L.; de Barros, B.; Kingdon, C.C.; Cliff, J.M.; Clark, T.G.; Mudie, K.; Dockrell, H.M.; Lacerda, E.M. Evidence of Clinical Pathology Abnormalities in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) from an Analytic Cross-Sectional Study. Diagnostics 2019, 9, 41. https://www.mdpi.com/2075-4418/9/2/41 (Full article available as PDF file)

Comparison of differential metabolites in urine of the middle school students with chronic fatigue syndrome before and after exercise

Abstract:

OBJECTIVE: To study the differential metabolites in urine and the characteristics of metabolic pathway of middle school students with chronic fatigue syndrome (CFS) before and after exercise, and then explain the metabolic mechanism of CFS.

METHODS: Eight male middle school students (age:17-19) with CFS were selected as the CFS group according to CFS screening criteria of the U.S. centers.At the same time, 8 male health students of the same age from the same school were selected as the control group. They were administrated to do one-time exercise on the improved Harvard step (up and down steps 30 times/min for 3 minutes). Their urine was collected before and after exercise, and the differential metabolites in urine were detected by liquid chromatography-mass spectrometry (LC-MS). The multidimensional statistical methods were used to analyze the metabolites by principal component analysis (PCA) and orthogonal projections to latent structures-discriminant analysis (OPLS-DA). Finally, MetPA database was used to analyze the metabolites and to construct the correlative metabolic pathways.

RESULTS: Compared with the control group, the creatine, indoleacetaldehyde, phytosphingosine and pyroglutamic acid were selected as differential metabolites and the contents of those were decreased significantly (P<0.05 or P<0.01) in CFS group before the step movement. However, 11 differential metabolites in CFS group were selected out after exercise, which were nonanedioic acid, methyladenosine, acetylcarnitine, capric acid, corticosterone, creatine, levonorgestrel, pantothenic acid, pyroglutamic acid, xanthosine and xanthurenic acid in sequence, the contents of methyladenosine and creatine were significantly increased (P<0.05) and the contents of the other 9 differential metabolites were significantly decreased (P<0.05 or P<0.01)compared with the control group.

The 15 differential metabolites mentioned above were input MetPA database in order to analyze the metabolic pathways weighted score.The results showed that the arginine-proline metabolism pathway disorders were detected in the CFS group before exercise, the marker metabolite was creatine. And 3 metabolic pathways disorder were detected in the CFS group after exercise, which were arginine-proline metabolism, biosynthesis of pantothenic acid and CoA, steroid hormone biosynthesis, and the marker metabolites, in turn, were creatine, pantothenic acid and corticosterone.

CONCLUSIONS: The disorder of arginine-proline metabolic pathway is detected in CFS middle school students before exercise intervention. After exercise, it can be detected that the steroid hormone biosynthetic metabolic pathway, pantothenic acid and CoA metabolic pathways also have metabolic disorders.

Source: Chi AP, Wang ZN, Shi B, Yang XF, Min RX, Song J. Comparison of differential metabolites in urine of the middle school students with chronic fatigue syndrome before and after exercise. [Article in Chinese] Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2018 Apr 8;34(4):340-344 349. doi: 10.12047/j.cjap.5633.2018.078.  https://www.ncbi.nlm.nih.gov/pubmed/30788942